Program Summary/Abstract This second renewal application of the Mayo Clinic Breast Cancer SPORE is being submitted with the vision that the burden of breast cancer can be reduced through the performance of innovative translational research addressing issues of high significance for women. The science of the SPORE includes four translational research projects. Project 1: ?Cancer risks for mutations in breast cancer predisposition genes? focuses on non-BRCA1/BRCA2 genes included in ?panel based? tests. Using the PROMPT registry, the investigators will define the penetrance of breast cancers associated with inactivating mutations, the clinical relevance of variants of uncertain significance, and pathological ?phenotype? of these mutations. Project 2: ?Therapeutic targeting of ER? in triple negative breast cancer (TNBC)? is based on Mayo investigator data that ER?, when expressed in TNBC, is prognostic, and that ER? agonists suppress proliferation through the TGF? pathway. This project culminates in a phase II study of estradiol in ER?+TNBC within the Translational Breast Cancer Research Symposium. Project 3: ?Measles virus based immunovirotherapy in the treatment of metastatic breast cancer? is based on pioneering work of Mayo investigators to develop a measles virus (MV) that expresses an immunostimulatory transgene (MV-NAP), and the synergistic antitumor activity of MV-NAP with PD-1 blockade. This project includes a MV-NAP phase I study, and development of additional preclinical data that will inform the clinical trial of the combination of MV-NAP and PD-1 blockade. Project 4: ?Pharmacogenomics of aromatase inhibitors (AI) in early stage postmenopausal breast cancer? is based upon the importance of estrogen levels in AI-treated women. The investigators plan secondary analyses of adjuvant AI trials to determine whether inadequate estrogen suppression is associated with cancer recurrence, followed by a genome-wide analysis to identify genetic variants associated with the ?optimal? estrogen threshold and then prospective validation in a clinical study. These research projects are supported by three highly interactive cores: Core A: Administrative Core, Core B: Biospecimen and Pathology Core, and Core C: Biostatistics, Bioinformatics, and Patient Registry Core. A Developmental Research Program will continue to identify and develop research projects that hold the greatest promise to advance to full SPORE projects, and a Career Enhancement Program will continue to identify and support faculty investigators in breast cancer translational research that have the greatest potential to become future SPORE leaders. The investigators, cores, and the research programs in the SPORE are all integrated in the Mayo Clinic Cancer Center. Collectively, our SPORE will make discoveries and translate them into the clinic for the benefit of women with, or at risk of breast cancer.